The anterior cingulate cortex (ACC) plays an important part in chronic pain states.
NMDA-receptor-dependent postsynaptic long-term potentiation (LTP) in the ACC sustains the affective component of the pain state.
Kainate-receptor-dependent presynaptic LTP in the ACC contributes to pain-related anxiety.
The mechanism for neuropathic pain is linked to the expression of LTP in the ACC.
Upregulation of GluN2B-containing NMDA receptors is found in chronic neuropathic pain conditions.
Calcium-stimulated adenylyl cyclase 1 is a potential target for future treatment of chronic pain and anxiety.
The anterior cingulate cortex (ACC) is activated in both acute and chronic pain. In this Review, we discuss increasing evidence from rodent studies that ACC activation contributes to chronic pain states and describe several forms of synaptic plasticity that may underlie this effect. In particular, one form of long-term potentiation (LTP) in the ACC, which is triggered by the activation of NMDA receptors and expressed by an increase in AMPA-receptor function, sustains the affective component of the pain state. Another form of LTP in the ACC, which is triggered by the activation of kainate receptors and expressed by an increase in glutamate release, may contribute to pain-related anxiety.
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This work is supported by grants from Xi'an Jiaotong University, China. M.Z. is supported by grants from the EJLB Fondation-CIHR (Canadian Institutes of Health Research) Michael Smith Chair in Neurosciences and Mental Health, the Canada Research Chair, the Canadian Institute for Health Research (MOP-258523), the Natural Sciences and Engineering Research Council of Canada (RGPIN 402555), the Azrieli Neurodevelopmental Research Program and Brain Canada. B.-K.K. is supported by the National Honor Scientist Program (NRF 2012R1A3A1050385) in Korea. G.C. is supported by grants from the UK Medical Research Council, the UK Biotechnology and Biological Sciences Research Council and the European Research Council.
The authors declare no competing financial interests.
- Acute pain
Pain that is associated with a noxious stimulus and that does not persist when the noxious stimulus is removed.
- Fear memory
A type of associative memory in which a fear response is triggered by a context or a neutral stimulus that was previously associated with an aversive event.
An affective state reflecting a feeling of unease, worry or fear.
- Chronic pain
Long-lasting pain that is associated with a chronic disease, or an aberrant type of pain that persists beyond recovery from disease or injury.
- Neuropathic pain
A type of chronic pain caused by a lesion or disease of the peripheral nervous system or the CNS.
- Fear conditioning
A behavioural task in which an animal learns to associate a neutral stimulus (for example, a tone) with an aversive event (for example, a footshock). See the glossary definition for 'fear memory'.
- Trace fear conditioning
A form of fear conditioning in which a time interval is interposed between the conditioned stimulus and the unconditioned stimulus.
- Affective component of the pain state
The feeling of unpleasantness that is associated with pain.
An abnormal type of pain that is caused by a stimulus that typically does not evoke pain.
A condition in which the level of pain arising from a particular painful stimulus is greater than would normally arise from that stimulus.
- Central sensitization
Increased responsiveness of nociceptive neurons in the CNS to their normal or subthreshold afferent input.
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Bliss, T., Collingridge, G., Kaang, BK. et al. Synaptic plasticity in the anterior cingulate cortex in acute and chronic pain. Nat Rev Neurosci 17, 485–496 (2016). https://doi.org/10.1038/nrn.2016.68
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